Kate Johnson

April 03, 2017

WASHINGTON, DC — A tiny subset of patients with multidrug-resistant metastatic colorectal cancer (mCRC) can do surprisingly well with a chemotherapy-free regimen targeting HER2 mutations, according to final results from the HERACLES A trial.

The study, presented at the American Association for Cancer Research annual meeting, showed that a dual HER2-blocking combination of trastuzumab (Herceptin, Genentech/Roche) and lapatinib (Tykerb, GlaxoSmithKline) in a group of 33 heavily pretreated patients resulted in clinical benefit (disease control) in 70% and an overall objective response rate of 30%.

Among these responders, 2 patients had complete response, "and 1 of these complete responders is still alive without evidence of disease at almost 36 months from the beginning of treatment…it's — I wouldn't say a cure — but I hope so," said investigator Silvia Marsoni, MD, from the Istituto di Candiolo in Candiolo, Torino, Italy, during a press conference.

Even though HER2-positive patients represent only 3% of the colon cancer population, "they are still an important little piece of the cake that can actually be targeted," she added, explaining that 75% of the study population had already been treated with 4 or more prior drugs, and all patients were resistant to cetuximab, the standard of care for mCRC.

"This is a sensational observation," noted Hans-Joachim Schmoll, MD, PhD, from Martin Luther University of Halle-Wittenberg, Germany, who was not involved in the study.

"Until now, in advanced colorectal cancer, systemic treatment with chemotherapy…has only very exceptionally induced complete responses in first-line treatment, most of it not long-lasting — and in last-line treatment this has never been reported before," he told Medscape Medical News.

"Since these patients are also those that do not respond to cetuximab therapy, we've got a new potential treatment for this population," said Dr Marsoni. "And there's really no toxicity. There was no grade 3 toxicity, we had one case of diarrhea and the others were fatigue, and 90% of patients were compliant with treatment. The patient on treatment for 36 months has no complaints whatsoever."

But zeroing in on the study patients' HER2 mutations and what drug combination to treat them with is a story in itself.

Dr Marsoni's team started with "avatars" — mice that had been transplanted with metastasized tumors from the patients with colorectal cancer. The mice were first treated with cetuximab — and only the nonresponders were selected for tumor DNA analysis.

Not surprisingly, there were KRAS, NRAS, and BRAF mutations, thought to present in roughly half of patients with mCRC. But there was also HER2 amplification. It would have been tempting to randomly select any of a handful of HER2-blocking drugs developed for breast cancer and try them in the patients with mCRC, but the researchers decided to go back to the avatars first.

That step made all the difference. It showed them that neither trastuzumab nor lapatinib did much for the avatars alone — but together they had synergy.

"The problem is we tend to go from the discovery to the clinic without an experimental [step] which will make us understand what is the complexity of the interaction between the tumor cells and their lineage — in this case breast vs colon cancer," Dr Marsoni explained.

The results "confirm HER2 as a druggable target in colorectal cancer," noted David M. Hyman, MD (who was not involved in the HERACLES A study), during an interview with Medscape Medical News.

Dr Hyman, director of Developmental Therapeutics at Memorial Sloan Kettering Cancer Center in New York City, presented a separate study at the meeting showing that using the investigational pan-HER–targeted therapeutic neratinib to block HER2 in 21 different cancers had variable efficacy depending on the type of cancer, and type of mutation.

The SUMMIT study, which included 125 patients, showed the best response rate for breast cancer, with biliary and cervical cancers showing an intermediate response rate and colorectal cancer showing none.

Commenting on his findings, he said, "these data show that you can't treat all HER2 mutations the same….There are true differences in the way these different cancers are programmed to respond to [HER2] inhibitors."

Referring to this as "tumor lineage," he said that "the majority of mutations will be influenced by their tumor lineage in a very significant way in terms of their druggability." However, others may not, he said.

"I don't think we are ready to reorganize the taxonomy of cancer by mutation alone. I wouldn't suggest that every patient go out and get HER mutational testing, but they're not being tested in isolation. The tests now are testing for hundreds of potentially actionable mutations simultaneously and so, if you can embed that in a highly multiplex test that looks for other biomarkers…"

So, why did HER2-amplified colon cancer respond to Dr Marsoni's trastuzumab/lapatinib combo and not Dr Hyman's investigational neratinib — all of them HER2 inhibitors?

"When you see HER2 mutations in colon cancer they're — not exclusively, but often — exclusive of other drivers like RAS mutations or even amplifications, so I think they are true drivers. We just need better techniques to drug the driver," suggested Dr Hyman.

Commenting on HERACLES A, Dr Schmoll concluded, "this is a very small, tiny subgroup, but the future of treatment in many tumors is the proper identification of the right patient for the right drug —  this is just an important example of this approach."

Still to be determined is the best timing for HER2 testing, said HERACLES A discussant  Rodrigo Dienstmann, MD, from Vall d'Hebron Institute of Oncology in Barcelona, Spain.

"Should it be done upfront before you offer [initial] therapy that will not produce response, or should it be in the acquired-resistance setting like in the HERACLES study where we know that HER2 is a major driver in tumor progression?"

It should be done for all patients with colorectal cancer, "but not in the first or second line now (probably after further trials), but definitely from third line on," recommended Dr. Schmoll. 

The HERACLES A study was funded by Associazione Italiana per la Ricerca sul Cancro; Roche and Novartis provided study drugs free of charge. Dr Marsoni disclosed that she participates in advisory boards for Igmyta, Merrymack, and Roche. This SUMMIT study was funded by Puma Biotechnology.  Dr Hyman consults for Atara Biotherapeutics, Chugai, CytomX, and Boehringer. He also receives research funding from AstraZeneca and Puma Biotechnology. Dr Schmoll has disclosed grants and personal fees from Roche, personal fees from Bayer, and personal fees from Amgen. Dr Dienstmann has disclosed no relevant financial relationships.

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